Neutralisation of SARS-CoV-2 by destruction of the prefusion Spike
JiandongHuo123∗YuguangZhao1∗JingshanRen1DamingZhou1Helen ME.Duyvesteyn1Helen M.Ginn6LoicCarrique1TomasMalinauskas1Reinis R.Ruza1Pranav NM.Shah1Tiong KitTan4PramilaRijal4NaomiCoombes5Kevin R.Bewley5Julia A.Tree5JulikaRadecke6Neil G.Paterson6PiyasaSupasa7…David I.Stuart169$
https://doi.org/10.1016/j.chom.2020.06.010
Summary
There are as yet no licenced therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric Spike whose receptor binding domain (RBD) recognises angiotensin-converting enzyme 2 (ACE2), initiating conformational changes that drive membrane fusion. We find that the monoclonal antibody CR3022 binds the RBD tightly, neutralising SARS-CoV-2 and report the crystal structure at 2.4 Å of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilising, CR3022 epitope is inaccessible in the prefusion Spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. Cryo-EM analysis confirms that incubation of Spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope may be useful therapeutically, possibly in synergy with an antibody blocking receptor attachment.
